The above-referenced application, U.S. PTO Ser. No. 10/231,767, filed on Aug. 28, 2003, discloses a device comprising a housing, wherein the housing comprises a reservoir member with a drug release port for release of at least a first therapeutic agent into a target tissue, said reservoir member having at least a first wall that is substantially impermeable to a first therapeutic agent to be placed therein, a sealing base for sealing said release port to a target tissue, wherein when said release port is sealed to a target tissue, a first therapeutic agent in said reservoir is substantially prohibited from release by said device other than through said release port into the target tissue, and an attachment mechanism to facilitate sealing of said release port to a target tissue, said attachment mechanism comprising at least one member of the group consisting of a sufficient amount of an adhesive for adhering said sealing base to a target tissue, a suture holder for engaging at least one suture operatively attached to the surrounding tissue, and an encircling band for engaging a fitting operatively attached to the surrounding target tissue.
Despite advances in screening and filtering of compounds during the drug development process, it is estimated that 99% of evaluated agents fail to reach clinical testing. Approximately 40% of the failures are due to poor pharmacokinetics and 11% to pre-clinical toxicity.1,2 The search for new drugs is time-consuming and very expensive. Many drugs with proven therapeutic benefit for site-specific disease cannot be used clinically because of unacceptable systemic toxicity.
The value of local administration of therapeutic agents to organ-confined disease is demonstrated by the continuing efforts to improve local delivery to the eye. The ocular volume constitutes less than 1% of the body volume. When therapeutic agents are administered systemically for intraocular disease, most of the effect of the drugs is on normal non-ocular tissue.
The treatment of most diseases today requires a careful balance between the therapeutic efficacy of any specific agent and the unwanted side effects to be expected from its use. The intervals between cycles of chemotherapeutic agents for malignant disease are necessary to allow the body to recover from unwanted systemic toxicity. This cycling of treatment may not be the most efficacious way to deliver therapy to the disease but it cannot be avoided. The development of bio-targeted agents promises some relief from the side effects of today's drugs on normal tissue. However, the costs associated with new agent development are enormous and their long-term side effects are not well understood.
Intraocular implants with sustained release of therapeutic agents were a great advance in the therapy of posterior segment (choroidal and retinal) ocular diseases. In most of these implants, the drug release rate is regulated mainly by the drug interaction with the polymer or coating membrane. The intravitreal route of drug delivery has limitations, however. If, as in the case of intraocular retinoblastoma, dissemination of tumor cells to the rest of the body is detrimental, then opening the eye for therapeutic reasons presents the risk of systemic dissemination of tumor cells. This limitation certainly applies to other tumors and other tissues. Moreover, intraocular procedures, regardless their purpose, require specialized expertise, and present inherent risks, such as endophthalmitis and retinal detachment.
U.S. Pat. Nos. 6,217,895; 6,001,386; 5,902,598; and 5,836,935, to Ashton et al. describe a surgically implantable device for local delivery of low solubility therapeutic agents in an internal portion of the body. The device comprises an inner core containing the drug isolated from the surrounding environment by a permeable coating polymer, which controls the release rate of the drug. The device delivers the drug in a multidirectional way from the implantation site, exposing the surrounding tissues to the delivered agent. It can be anchored to a tissue but no methods to seal it to a targeted tissue are disclosed.
Several studies were conducted to study potential advantages of the subconjunctival (periocular) injections of drugs over the topical (eyedrops) and systemic (intravenous) routes. Subconjunctival injections explore the diffusion properties of the sclera to drugs. Different drugs have been tested aiming for a improved pharmacokinetics in different layers of the eye. The results showed that a large variety of agents up to 40 kDa in size can diffuse across the sclera, in part because of the sclera's lack of binding sites. Similar evidence is available for several other organs and tissues. The injection of solutions containing drugs around or inside a tissue is a useful method to deliver drugs if their therapeutic effect in that tissue is transient, but repeated injections bring discomfort, pain and a higher risk of complications.
Moreover, subconjunctival injections lack specificity because the injected drugs diffuse to all the surrounding tissues, e.g. sclera, optic nerve, extraocular muscles and orbital fat and will interact in both a therapeutic and toxic way with all of them.
The subconjunctival delivery route does not address the fact that drugs have an acceptable rate of complications based on the benefits they provide to pathologic organs and tissues nor does it address the fact that the toxicity tolerated by normal tissues and organs is lower. The present invention described below can provide target-specificity based on topographic selectiveness even for nonspecific agents at the molecular level. As an example, it was shown that periocular injections of carboplatin can lead to ocular motility problems, including restriction of the eye movements, after a certain period following the injection. These complications are related to fibrosis of the periocular tissues caused by the inflammatory-inductor effect of carboplatin on normal surrounding tissue.(1)
U.S. Pat. Nos. 6,416,777 and 6,413,540, to Yaacobi et al., disclose devices that once positioned underneath the Tenon's capsule, in contact to the sclera, deliver agents to the eye. The device has a geometry that facilitates its insertion and placement in the sub-Tenon's space, and reference is made to a method to place and hold it under the inferior oblique muscle, avoiding its dislocation from its original location and proportioning its positioning near the macular area. No references are made to methods to hermetically seal it to the sclera or to the targeted tissue. Moreover, the design of those devices does not accommodate methods to carry more than one agent, as in a bi-compartmental reservoir of the present invention described below, neither does it disclose refilling ports such as those of the present invention described herein to allow refilling or recharging of the liquid therapeutic agents.
The prior art, albeit providing methods to improve and sustain the drug delivery from an implantation site, does not recognize the need of sealing the drug delivery reservoir to the targeted tissue. Therefore, if highly cytotoxic agents are used, as are required for the treatment of intraocular retinoblastoma, exposure of surrounding tissues such as the optic nerve and extraocular muscles to the delivered agents can lead to unacceptable toxicity and limit the use of important drugs shown in vitro to be efficacious against that condition.
Slow release technologies provide control over the availability of the drug to the tissue and can prolong its therapeutic life. The present invention does not exclude the use of slow drug-release technologies. Instead, they can be incorporated as a way to improve the pharmacokinetics of agents selectively delivered to targeted tissues.
Over the past decades significant experience with periocular implants has been achieved through the established practice of encircling the eye to treat retinal detachment and by the wide use of filtration devices for the surgical therapy of glaucoma. Many polymers were tested for that purpose, and the experience accumulated over the years showed that encapsulation of the implant invariably occurs after periocular implantation. Indeed, even for largely used biocompatible medical products such as silicone, it was shown that the encapsulation process starts as soon as 3 days following insertion.(2-8) A fibrotic reaction to a prosthesis or to an structural implant is not so harmful. Instead, it may be even desired to provide mechanical stability to the implant and enhance its structural function. Nevertheless, the fibrotic reaction can lead to the extrusion of the implant from the orbit. To address that problem, adhesives have been proposed as a component of the present invention described herein to enhance implant stability.(9-11) In the case of buckling elements, adhesives can be applied to the surface of the implant in contact with the sclera, in addition to the conventional sutures placed to anchor the implant to the eyeball. Ricci and Ricci demonstrated good compatibility of buckling implants in apposition to the sclera using a cyanoacrylate derivative.(12) Cyanoacrylate has been approved for human use as tissue adhesive, n-Butyl-2-Cyanoacrylate monomer, (Indermil™ Tissue Adhesive, Tyco Healthcare Group, LP, Norwalk, Conn.). The biocompatibility and safety of derivatives of cyanoacrylate also permitted its approval to embolize malformed blood vessels after injection through a catheter, n-Butyl Cyanoacrylate (TRUFILL®, Cordis Neurovascular, Inc., Miami Lakes, Fla.).
As for buckling elements, drug delivery devices need to be anchored in place. Olsen et al., studying a device positioned in contact with the sclera, but not anchored or sealed to the scleral surface, but only positioned between the extraocular muscle and the sclera, encountered moderate migration of the device from its original site of implantation in 9 out of 9 implanted eyes.(13) Yaacobi et al. demonstrated that by implanting non-anchored or attached devices, a fibrous capsule and minimal inflammation could be found histologically. (14)
The Need For A Sealed Junction: If the possibility exists of drug leakage into surrounding tissue via a non-sealed device-tissue junction then this fact excludes the possible use of some important therapeutic agents.
The lack of a way to seal the device to the tissue would not only affect the way the stability and release profile of the active agent from its formulation, but it would also allow immunoglobulins, albumin, inflammatory cells and other components of plasma to interfere with the agent's availability and stability profiles. In addition, encapsulation of such system resulting from scar tissue formation between the drug reservoir and the organ surface could significantly change the pattern of drug release by altering important determinants of diffusion through the membrane surface, such as thickness and porosity of the membrane. The interposition of a second membrane, i.e. a fibrous capsule, between the drug reservoir and the targeted surface may also result in different diffusion coefficient since inflammatory membranes do not present the same porous characteristics as the sclera.(15) To overcome this problem, the use of an adhesive in the present invention represents a viable alternative to create a liquid-tight seal between the drug delivery device and the targeted surface.
In view of the aforementioned, there is a need for an invention that can improve the efficacy, tolerability and effectiveness of locally administered therapeutic agents. There is also a need for a method of administration that can sustain stability, delivery and effect, and control toxicity of therapeutic agents delivered thereby. The present invention, described herein achieves the forgoing goals, and can also expand the applicability of therapeutic agents that have been abandoned or had limited clinical use. In addition, the present invention can provide a stable and controlled environment where both delivery of new drugs and technologies of sustained drug release can be improved.